A second pedigree with amyloid-less familial Alzheimer’s disease harboring an identical mutation in the amyloid precursor protein gene (E693delta)

Abstract

A 59-year-old woman developed early-onset, slowly progressive dementia and spastic paraplegia. positron emission tomography (PET) imaging revealed a large reduction in the level of glucose uptake without amyloid deposition in the cerebral cortex. We identified a homozygous microdeletion within the amyloid β (Aβ) coding sequence in the amyloid precursor protein (APP) gene (c.2080_2082delGAA, p.E693del) in three affected siblings and a heterozygous microdeletion in an unaffected sibling. The identical mutation was previously reported in the first Alzheimer’s pedigree without amyloid deposits. Furthermore, an increase in highmolecular- weight Aβ-reactive bands was detected in the patient’s CSF. Our findings suggest that soluble Aβ- oligomers induce neuronal toxicity, independent of insoluble Aβ fibrils.